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Weill Medical College of Cornell University, E. W. Bourne Behavioral Laboratory, White Plains, New York 10509
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The steroid hormone estradiol
decreases meal size by increasing the potency of negative-feedback
signals involved in meal termination. We used c-Fos
immunohistochemistry, a marker of neuronal activation, to investigate
the hypothesis that estradiol modulates the processing of
feeding-induced negative-feedback signals within the nucleus of the
solitary tract (NTS), the first central relay of the neuronal network
controlling food intake, and within other brain regions related to the
control of food intake. Chow-fed, ovariectomized rats were injected
subcutaneously with 10 µg 17-
estradiol benzoate or sesame oil
vehicle on 2 consecutive days. Forty-eight hours after the second
injections, 0, 5, or 10 ml of a familiar sweet milk diet were presented
for 20 min at dark onset. Rats were perfused 100 min later, and brain
tissue was collected and processed for c-Fos-like immunoreactivity.
Feeding increased the number of c-Fos-positive cells in the NTS, the
paraventricular nucleus of the hypothalamus (PVN), and the central
nucleus of the amygdala (CeA) in oil-treated rats. Estradiol treatment
further increased this response in the caudal, subpostremal, and
intermediate NTS, which process negative-feedback satiation signals,
but not in the rostral NTS, which processes positive-feedback gustatory signals controlling meal size. Estradiol treatment also increased feeding-induced c-Fos in the PVN and CeA. These results indicate that
modest amounts of food increase neuronal activity within brain regions
implicated in the control of meal size in ovariectomized rats and that
estradiol treatment selectively increases this activation. They also
suggest that estradiol decreases meal size by increasing feeding-related neuronal activity in multiple regions of the
distributed neural network controlling meal size.
ingestive behavior; meal size; satiation; nucleus of the solitary tract; amygdala; paraventricular nucleus of the hypothalamus; females
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THE STEROID HORMONE ESTRADIOL exerts a potent, physiological, inhibitory effect on feeding in a variety of species (16, 19, 42). Estradiol-induced reductions in feeding are expressed as reductions in meal size, not meal frequency (17). This effect of estradiol is especially prominent in female rats, which decrease meal size 15-25% during the estrous phase of the ovarian cycle compared with diestrous and proestrous phases (2, 10, 12, 13, 27). Meal size is increased by 30-50% in untreated ovariectomized rats, but it is normal in ovariectomized rats treated with physiological concentrations of estradiol (2, 17). Thus estradiol appears to play an important, normal role in the control of meal size in female rats.
Several studies indicate that estradiol increases the satiating potency of negative-feedback controls of meal size that are elicited by postingestive actions of food consumption. In ovariectomized rats, the satiating potency of the gut peptide CCK is increased by estradiol treatment (1, 4, 20, 28), and antagonism of endogenous CCK with devazepide increases meal size during estrus but not during diestrus (1, 11). It is unclear, however, where or how estradiol influences the central processing of negative-feedback controls of meal size. Some (5, 6), but not all (8; Hrupka BJ, Smith GP, and Geary N, unpublished observations), studies implicate the paraventricular nucleus of the hypothalamus (PVN) as a key site.
Neurons that may participate in the control of feeding have been localized by immunohistochemical detection of c-Fos protein, the product of the immediate-early gene c-fos. The accumulation of c-Fos in the nuclei of some populations of activated neurons allows c-Fos measurement to be used to characterize the distribution and number of individual neurons activated during various functional states. Application of this technique in male rats has revealed that feeding increases neuronal activation in several brain regions including the nucleus of the solitary tract (NTS), area postrema (AP), dorsal motor nucleus of the vagus, hypoglossal nucleus, and the lateral parabrachial nucleus (9, 14, 15, 31, 33, 40, 43). Examination of feeding-induced c-Fos expression in female rats may suggest whether estradiol inhibits meal size by modulating neuronal activity in one or more brain regions shown previously to be activated by feeding. Our aim here, therefore, was to use c-Fos immunohistochemistry to determine whether estradiol modulates feeding-induced neuronal activation within some of the brain regions implicated in processing feeding-related negative-feedback signals controlling meal size. Specifically, we hypothesized that estradiol treatment in ovariectomized rats increases the number of feeding-induced c-Fos-positive cells within the NTS, the first central target of vagal afferent fibers mediating the satiating action of CCK and other satiation signals.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals. Thirty-eight adult female Long-Evans rats (Charles River Breeding Laboratories, Wilmington, MA; weighing 200-225 g at study onset) were housed individually in hanging cages with wire mesh floors. Rats were given free access to Purina rat chow and tap water unless otherwise noted. The room was maintained at 20 ± 2°C with a 12:12-h light-dark cycle (lights off at 1400). A red 25-W incandescent bulb provided dim illumination during the dark phase. Rats were adapted to the housing conditions for 1 wk before surgery and testing.
Ovariectomy. Rats were anesthetized by intraperitoneal injection of a mixture of 70 mg/kg ketamine (Ketaset, Fort Dodge, Fort Dodge, IA) and 4.5 mg/kg xylazine (Rompun, Mobay, Shawnee, KS), and they were bilaterally ovariectomized using an intra-abdominal approach.
Adaptation to milk diet. Beginning 1 day after ovariectomy, rats were given free access to a milk diet, in addition to chow and water, for 4 days. The milk diet consisted of sweetened condensed milk (Eagle Brand, Borden, Tarrytown, NY) diluted 1:2 with tap water (6.15 kJ/ml). By the end of this adaptation period, rats consumed 62 ± 10 ml of milk per day. Two days later, rats were given a small volume of the milk diet to determine whether they would readily consume it during a brief-access test. At dark onset (1400), chow and water were removed, and rats were given 10 ml of the milk diet in graduated burets (±0.1 ml) fitted with drip-resistant sipper tubes. After 20 min, the burets were removed, the volume of milk consumed was recorded, and chow and water were returned. All rats avidly consumed the milk diet (average consumption = 9.3 ± 0.2 ml) during this brief-access test.
Estradiol treatment.
Eight days after ovariectomy, rats were assigned to two groups of
approximately equal body weight (n = 19 per group). One group received intrascapular subcutaneous injections of 10 µg 17-
estradiol-3-benzoate (Sigma Chemical, St. Louis, MO) in 100 µl sesame
oil vehicle (Sigma), and the other group received 100 µl vehicle
alone. Injections were administered at 1000 on 2 consecutive days. This
schedule of estradiol treatment induces behavioral indications of
estrus in ovariectomized rats. It reduces food intake and meal size for
2-5 days (18) and, when progesterone is injected 2 days after the second estradiol injection, it increases sexual
receptivity (29, 35). The present feeding test was done 2 days after the second estradiol injection, when these effects are
maximal. Estradiol treatment also normalizes the body weight gain
postovariectomy (2, 18). Thus body weight was recorded every 2-3 days throughout the experiment to verify the efficacy of
estradiol treatment.
Feeding test. Two days after the second estradiol or vehicle treatment, chow and water were removed at dark onset (1400), and rats were then given access to burets filled with 0, 5, or 10 ml of milk. At 1420, the burets were removed, and the volume of any unconsumed milk was recorded. For inclusion in the experiment, rats were required to consume at least 95% of the volume of milk presented. Two rats failed to meet this criterion (one from each hormone treatment group), resulting in a final sample size of 36 rats (n = 6 per condition).
Perfusion and tissue collection.
At 1600, rats were overdosed with pentobarbital sodium (65 mg/kg ip;
Nembutal, Butler, Columbus, OH) and transcardially perfused with 100 ml
of isotonic heparinized saline containing 0.5% NaNO
Immunohistochemistry. Every second hindbrain section and every fourth forebrain section were processed for c-Fos-like immunoreactivity. Free-floating tissue sections were washed in PBS, blocked in a PBS solution containing 0.2% Triton X-100 and 1% BSA for 30 min, washed in a PBS solution containing 0.5% BSA (PBS/BSA), and incubated 20 h at room temperature with rabbit polyclonal anti-c-Fos peptide antisera (Ab-5, Oncogene Sciences, Cambridge, MA) diluted 1:20,000 in PBS/BSA. Sections were then washed in PBS/BSA and incubated for 1 h at room temperature with a biotinylated anti-rabbit goat antibody (Vector Laboratories) diluted 1:200 in PBS/BSA. Bound secondary antibody was amplified during a 1-h incubation of the sections in an avidin-biotin complex (Vectastain ABC Elite Kit, Vector Laboratories) diluted 1:50 in PBS/BSA. Antibody complexes were visualized by immersing the tissue in 2% diaminobenzidine (Kirkegaard and Perry Laboratories, Gaithersberg, MD) for 5 min. This reaction was stopped by rinsing the sections in PB. Sections were then mounted on microscope slides and coverslipped.
Quantification of c-Fos-like immunoreactivity. The presence of c-Fos-like immunoreactivity was quantified using Image-Pro Plus software (V3.0, MediaCybernetics, Gaithersberg, MD). A constant set of threshold criteria based on optical density, object shape, and object size was used to identify c-Fos-positive cells containing dark, punctate, nuclear staining. c-Fos-like immunoreactivity was examined in four regions of the NTS: caudal NTS (cNTS); including all sections caudal to the AP; subpostremal NTS (spNTS); including sections in which the AP was visible; intermediate NTS (iNTS); including sections rostral to the AP in which the NTS abutted the fourth ventricle; and rostral NTS (rNTS); including sections in which the NTS diverged from the fourth ventricle. Every other hemisection through each of these regions of the NTS was quantified. In each section, the medial-lateral and dorsal-ventral borders of the NTS were delineated based on the templates contained in the Paxinos and Watson's (32) atlas, and only c-Fos-positive cells within these borders were counted (see Fig. 2). The AP was also examined. Due to the lack of c-Fos-positive cells within the AP, only the section containing its maximal extent was quantified. Every other hemisection through the PVN and CeA was also quantified. The borders of these nuclei were also defined using anatomic landmarks (32), and only c-Fos-positive cells within these borders were counted (see Fig. 5).
Statistical analysis. Data are presented as means ± SE. Changes in body weight following ovariectomy and estradiol or vehicle treatment were analyzed using a mixed-design ANOVA, with hormone as the between-subjects variable and time as the within-subjects variable. The numbers of c-Fos-positive cells were analyzed using two-factor ANOVAs (hormone treatment by volume of milk consumed) in each brain region of interest. When significant effects were detected by ANOVA (P < 0.05), differences between individual means were examined with Tukey's honestly significant difference test.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Body weight.
Estradiol treatment significantly reduced weight gain compared with
untreated ovariectomized rats, F(2,68) = 14.82, P < 0.0001 (Fig.
1).
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Caudal brain stem c-Fos expression.
Milk consumption increased c-Fos-like immunoreactivity in each region
of the NTS. c-Fos expression was maximal in the cNTS, spNTS, and iNTS
and minimal in the rNTS (Fig. 2). Volume
of milk consumed and estradiol treatment interacted to increase
c-Fos-like immunoreactivity in the cNTS, spNTS, and iNTS,
F(2,30) = 3.99-4.55, all
Ps < 0.05 (Figs. 3 and
4). In each of these regions, estradiol treatment increased the number of c-Fos-positive cells induced by
consumption of 5 or 10 ml of the milk diet (P < 0.05),
but it had no effect in the unfed (0 ml) condition (Fig. 4,
A-C). This modulation of feeding-induced c-Fos by
estradiol in the NTS was regionally specific as estradiol treatment did
not affect the number of c-Fos-positive cells in the rNTS,
F(2,30) = 1.49, P > 0.05 (Fig. 4D). In estradiol-treated rats, milk consumption induced a volume-dependent increase in c-Fos expression in the cNTS,
spNTS, and iNTS. That is, consumption of 10 ml of milk induced more
c-Fos expression than consumption of 5 ml of milk in each region
(P < 0.05). The amount of c-Fos also appeared to
increase with increasing volumes of milk consumed in vehicle-treated
rats, but this failed to reach statistical significance
(P > 0.05).
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Forebrain c-Fos expression.
Milk consumption increased c-Fos-like immunoreactivity in the PVN and
CeA (Figs. 5, C-F, and
6). Volume of milk consumed and estradiol
treatment interacted to increase c-Fos-like immunoreactivity in both
the PVN, F(2,28) = 12.75, P < 0.0001, and CeA,
F(2,30) = 4.37, P < 0.05. In both regions, estradiol treatment increased the number of
c-Fos-positive cells induced by consumption of 5 or 10 ml of the milk
diet (P < 0.05), but it had no effect in the unfed (0 ml) condition (Fig. 6). Also, in both regions, milk consumption-induced
c-Fos expression was volume dependent in estradiol-treated rats
(P < 0.05) but not in vehicle-treated rats
(P > 0.05). There were no apparent differences in the
density of c-Fos-positive cells in the magnocellular or parvocellular
subdivisions of the PVN or within the CeA (data not shown).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The fundamental control of meal size is thought to be exerted by the integration of positive- and negative-feedback signals produced by the action of ingested food on preabsorptive receptors (19, 39). These are called the direct controls of meal size. Other controls of meal size, including those related to the size of the adipose depot, circadian rhythms, or ovarian rhythms, are thought to modulate the actions of direct controls and, therefore, are called indirect controls. Estradiol appears to mediate the indirect control of meal size exerted by ovarian rhythms (2, 17) by increasing the potency of negative-feedback signals involved in the direct control of meal size (1, 11) rather than by modulating the potency of positive-feedback signals arising from oral food stimuli (21, 24). Here, we used c-Fos immunohistochemistry to investigate the hypothesis that estradiol increases feeding-induced neuronal activation within the NTS, the first central site to receive vagal negative-feedback signals from the gastrointestinal tract, of ovariectomized rats. There were three main findings. First, consumption of the milk diet increased the number of c-Fos-positive cells throughout the NTS and in the PVN and the CeA, relative to unfed controls. Second, amounts of food comparable to the size of spontaneous meals were sufficient for this response. Finally, and most relevant to our hypothesis, estradiol treatment increased the number of c-Fos-positive cells induced by consumption of the milk diet in each of these brain regions, except the rostral subdivision of the NTS. We discuss the implications of these data for the study of the neural control of meal size in general and the influence of estradiol on meal size in particular.
Neural control of meal size. Consumption of 5 and 10 ml of sweet milk induced expression of c-Fos protein throughout the NTS and in the PVN and the CeA of nondeprived, chow-fed ovariectomized rats. These data have several implications for the analysis of the neural control of feeding. First, although somewhat similar patterns of c-Fos expression have been reported in male rats consuming either chow (14, 31, 33) or liquid diets (9, 15, 33, 40), in those studies, rats were food deprived for extended periods (14-20 h) and, therefore, consumed unusually large meals. For example, c-Fos was shown to increase within the NTS in response to meals of 5-10 g of chow or 25-30 ml of sweetened liquid diet (33, 43). These meal sizes are considerably larger than spontaneous meals of these types of diets (2, 12, 13, 21, 26, 41). Our findings extend these reports by demonstrating for the first time that ingestion of as little as 5 ml of liquid food is sufficient to increase c-Fos-like immunoreactivity in several brain sites. This appears to be the first report that c-Fos induction can be elicited by ingestion of only a fraction of a full meal, which typically averages 10 ml or more under our test conditions. Furthermore, it is comparable to the size of spontaneous meals in female rats maintained on similar liquid diets.
In the present study, the numbers of c-Fos-positive cells in the cNTS, spNTS, and iNTS, as well as in the PVN and CeA, increased when estradiol-treated ovariectomized rats consumed 10 rather than 5 ml of milk. Our NTS data parallel Rinaman et al.'s (33) report of progressive increases in the proportion of catecholaminergic cells in the NTS that express c-Fos when male rats ingested increasing volumes of liquid food. Such graded responses suggest that c-Fos expression reflects the intensity of the neural representation of the satiating potency of the food ingested in these brain regions. Indeed, in Rinaman et al.'s (33) study, the percentage of catecholaminergic cells in the NTS expressing c-Fos correlated closely with the weight of gastric contents in rats consuming chow, liquid diet, or dilute liquid diet. Thus c-Fos expression may be used to localize and index quantitatively neural processes mediating the graded negative-feedback and resultant graded intensity of satiation induced by ingested food (30, 39). Negative-feedback signals produced by gastrointestinal food stimulation activate neural signals that project to the cNTS, spNTS, and iNTS (see Fig. 2). Thus the robust, graded increases in c-Fos expression within these regions of the NTS that were produced by consumption of the milk diet are likely to be related to the intensity of these signals. In contrast, consumption of the milk diet produced only a small nongraded increase in c-Fos expression in the rostral region of the NTS, which is the first central target of the positive-feedback signals related to sweet taste (41). This apparent difference in the efficacy of oral and postingestive feedbacks may reflect the relatively brief duration or the familiarity of the gustatory stimulation. Graded increases in c-Fos expression were also observed in the PVN and CeA of estradiol-treated rats. This appears to be the first report that feeding increases c-Fos expression in the PVN or CeA and extends many previous data linking the PVN and CeA to the control of food intake (3, 7). Our data do not demonstrate whether the PVN and CeA were activated solely by ascending inputs from the NTS or whether other neuronal pathways were involved. Finally, milk ingestion failed to increase c-Fos expression within the AP, or the hypoglossal nucleus, areas of the caudal brain stem in which food has been reported to increase c-Fos expression (9, 14, 15, 33). Increased c-Fos expression has been reported in these areas, however, only after comparatively large amounts of food intake. For example, Rinamen et al. (33) reported increased c-Fos expression in the NTS and AP in schedule-fed rats after ingestion of 10 g of chow or 25 ml of liquid diet but not after ingestion of 10 ml of the liquid diet. It is apparent, then, that different amounts of feeding under different conditions can result in qualitative, as well as quantitative, differences in c-Fos expression. The functional significance of this is not clear. Finally, as previously noted (33), food ingestion did not increase c-Fos expression within the ventrolateral medulla. This is interesting because estradiol appears to decrease meal size in part by increasing the satiating potency of CCK (1, 4, 11, 20), and CCK injection has been shown to increase c-Fos expression in the ventrolateral medulla (34).Estradiol and meal size. Estradiol treatment increased feeding-induced c-Fos-like immunoreactivity in the cNTS, spNTS, and iNTS, the PVN, and the CeA. The ability of estradiol to increase feeding-induced c-Fos expression in the NTS areas that process feeding-related negative-feedback signals (36) suggests that estradiol may decrease meal size by increasing the potency of these signals. The increases in c-Fos expression in the PVN and CeA may reflect further processing of the same controls (7).
That estradiol failed to increase feeding-induced c-Fos in the rNTS, which receives predominantly gustatory afferents, demonstrates that its effect is selective, not global. This is consistent with the failure of estradiol to affect two indexes of the control of feeding by oropharyngeal food stimuli, the initial rate of licking of sucrose solutions by real-feeding rats (24) and the amount of sucrose ingested by rats sham feeding with open gastric cannulas (21). Estradiol also failed to induce c-Fos-like immunoreactivity in unfed control rats (0 ml milk condition) in each brain region examined here. Another example of the selectivity of the effect of estradiol on c-Fos expression is that estradiol treatment in ovariectomized rats failed to modulate c-Fos-like immunoreactivity induced by a dose of lithium chloride that is sufficient to produce a conditioned taste aversion (23). Together, these findings suggest that estradiol's ability to modulate neuronal activity within these regions is dependent on inputs generated by negative-feedback stimuli resulting from food ingestion. Our results do not disclose the site(s) where estradiol acted to increase feeding-induced c-Fos expression. The NTS, PVN, and CeA are each candidate sites as each area contains estrogen receptors (22, 37, 38). Alternatively, estradiol may have acted on receptors elsewhere and indirectly affected neural activity in these areas. It is interesting to note in this context that estradiol treatment appeared to induce larger increases in feeding-stimulated c-Fos expression in the PVN and CeA (51 and 47%, respectively) than in the NTS (28-37%). It is possible that this reflects a relative synaptic proximity of the PVN and CeA neurons expressing c-Fos, compared with the NTS neurons expressing c-Fos, to the neurons containing the critical estrogen receptors, wherever they are located. It is also possible that this differential sensitivity is related to the larger number of estrogen receptors in the PVN and CeA than in the NTS (37). In conclusion, the present data provide novel information regarding the central neural control of meal size in female rats. Small amounts of feeding (5 or 10 ml of sweet milk) induced c-Fos expression in the cNTS and other brain areas. Consistent with our hypothesis, estradiol treatment that reduces meal size in ovariectomized rats (2, 17) increased this effect of feeding on c-Fos expression in cNTS. Thus estradiol may accelerate meal termination by amplifying the neural response of these brain regions to negative-feedback signals mediating the direct control of meal size elicited by gastrointestinal actions of ingested food. We also demonstrated that feeding induced, and estradiol treatment increased, c-Fos in the PVN and in the CeA, suggesting that each of these areas may also contribute to satiation and its control by estradiol.Perspectives
Estradiol potently reduces meal size in rats (2, 10, 12, 13, 17, 27) and may inhibit appetite in women (16, 19). Estradiol's inhibitory effect on feeding in rats appears to be mediated by increases in the satiating potency of negative-feedback signals generated by food ingestion (1, 4, 11, 20, 28). The data reported here identify three brain regions that may be involved in the neural processing that results in such increases in satiating potency, the NTS, PVN, and CeA. Although the specific roles of the neurons in these regions remain obscure, the phenomena that we report appear to present several opportunities to advance understanding of the neural control of satiation. One issue concerns the functional interrelationships of the activated neurons in NTS, PVN, and CeA. The NTS is clearly furthest downstream in terms of centripetal vagal projections, but NTS neurons also receive descending inputs from the PVN and amygdala so it may be upstream in the circuitry involved in the c-Fos responses identified here. Electrophysiological recordings or lesion studies may suggest answers. Another question concerns the functional contribution of the additional cells that are activated in estradiol-treated rats. Is it identical to that of the additional cells that are activated by ingestion of more food? Further phenotyping of these cells should help resolve this question. For example, in male rats, increased food ingestion increased the percentage of catecholaminergic cells in the NTS that expressed c-Fos (33). Thus it would be interesting to know, first, if feeding stimulated similar proportions of catecholaminergic cells in male and female rats and, second, if the supplemental cells recruited in estradiol-treated rats were also catecholaminergic.| |
ACKNOWLEDGEMENTS |
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We thank Dr. G. Smith for constructive criticism of the penultimate draft.
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FOOTNOTES |
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This work was supported by National Institutes of Health Grant DK-54523 (N. Geary) and a Medical Research Council of Canada Fellowship (L. A. Eckel).
Address for reprint requests and other correspondence: L. A. Eckel, Dept. of Psychology, Florida State Univ., Tallahassee, FL 32306-1270 (E-mail: eckel{at}psy.fsu.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 25 January 2001; accepted in final form 23 April 2001.
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TOP
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METHODS
RESULTS
DISCUSSION
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estradiol-treated rats greater than vehicle-treated
rats, P < 0.01.
